Project Summary/Abstract Tissues inherently interact mechanically with their surrounding matrix, but tissue engineering materials have not fully exploited this interaction to enhance integration with the human body. Moreover, only a few materials have been developed that allow control of drug delivery through mechanical forces, and existing methods use synthetic polymers which have limited potential for tissue integration or use mechanically weak hydrogels. The goal of the research plan is to develop mechanically active and tunable fibers of extracellular matrix proteins that leverage mechano-biochemical properties to control cell behavior in cardiovascular tissue engineering applications. The research plan proposes to develop a new class of materials that could improve long-term patency of vascular grafts by delivering bioactive molecules that encourage endothelialization in response to mechanical stimuli, while integrating with tissues more easily than synthetic polymers. The mechanical properties of the material will be tuned by altering the composition. Extracellular matrix fibers of varied compositions will be generated through wet spinning and mechanically tested in a wet and dry state using custom-built and Instron tensile testers. This will allow us to determine the relationship between protein content and mechanical properties like modulus, strength, and toughness in order to generate fibers with specific properties. New mechanosensitive interactions between extracellular matrix proteins and their ligands, as well as the impact of these interactions on cell behavior and signaling will be identified. To do this, extracellular matrix fibers will be stretched and binding of proteins to the fibers will be observed through immunostaining. The interactions identified could be new mechanisms through which cell detect the mechanics of their environment. Protein engineering will be used to generate therapeutic proteins that release from extracellular matrix fibers in response to defined mechanical stimuli, which could promote endothelialization of the material. The material could be used to enhance tissue integration and improve long term outcomes in vascular grafts. Completing this project will help the applicant achieve her career goals of becoming a leading industrial researcher because of the critical thinking, experimental design, and new technical skills she will gain in cell signaling, cell behavior, and protein engineering. The applicant will also improve her career trajectory by enhancing her communication skills and conceptual knowledge through writing research papers, attending and presenting at conferences and seminars, and running journal clubs. The supportive and collaborative environment of the Boston University Biomedical Engineering department, as well as the relevant expert knowledge of her Sponsor, Co-sponsor, and collaborators, will help the applicant successfully complete the training and research plans.